Epidemiology of multiple sclerosis Leray, E.; Moreau, T.; Fromont, A. ...
Revue neurologique,
January 2016, 2016-Jan, 2016-01-00, 20160101, 2016-01, Letnik:
172, Številka:
1
Journal Article
Recenzirano
Multiple sclerosis (MS) is the most frequently seen demyelinating disease, with a prevalence that varies considerably, from high levels in North America and Europe (>100/100,000 inhabitants) to low ...rates in Eastern Asia and sub-Saharan Africa (2/100,000 population). Knowledge of the geographical distribution of the disease and its survival data, and a better understanding of the natural history of the disease, have improved our understanding of the respective roles of endogenous and exogenous causes of MS. Concerning mortality, in a large French cohort of 27,603 patients, there was no difference between MS patients and controls in the first 20 years of the disease, although life expectancy was reduced by 6–7 years in MS patients. In 2004, the prevalence of MS in France was 94.7/100,000 population, according to data from the French National Health Insurance Agency for Salaried Workers (Caisse nationale d’assurance maladie des travailleurs Salariés CNAM-TS), which insures 87% of the French population. This prevalence was higher in the North and East of France. In several countries, including France, the gender ratio for MS incidence (women/men) went from 2/1 to 3/1 from the 1950s to the 2000s, but only for the relapsing–remitting form. As for risk factors of MS, the most pertinent environmental factors are infection with Epstein-Barr virus (EBV), especially if it arises after childhood and is symptomatic. The role of smoking in MS risk has been confirmed, but is modest. In contrast, vaccines, stress, traumatic events and allergies have not been identified as risk factors, while the involvement of vitamin D has yet to be confirmed. From a genetic point of view, the association between HLA-DRB1*15:01 and a high risk of MS has been known for decades. More recently, immunogenetic markers have been identified (IL2RA, IL7RA) and, in particular thanks to studies of genome-wide associations, more than 100 genetic variants have been reported. Most of these are involved in the immune response and often associated with other autoimmune diseases. Studies of the natural history of MS suggest it is a two-phase disease: in the first phase, inflammation is focal with flares; and in the second phase, disability progresses independently of focal inflammation. This has clear implications for therapy. Age may also be a key factor in the phenotype of the disease. In conclusion, France is a high-risk country for MS, but it only slightly reduces life expectancy. MS is a multifactorial disease and the implications of immunogenetics are major. Preventative approaches might be derived from knowledge of the risk factors and natural history of the disease (smoking, vitamin D).
It is well documented that disability accumulation in multiple sclerosis is correlated with axonal injury and that the extent of axonal injury is correlated with the degree of inflammation. However, ...the interdependence between focal inflammation, diffuse inflammation and neurodegeneration, and their relative contribution to clinical deficits, remains ambiguous. A hypothesis might be that early focal inflammation could be the pivotal event from which all else follows, suggesting the consideration of multiple sclerosis as a two-stage disease. This prompted us to define two phases in the disease course of multiple sclerosis by using two scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: an early phase, ‘Phase 1’, from multiple sclerosis clinical onset to irreversible Disability Status Scale 3 and a late phase, ‘Phase 2’, from irreversible Disability Status Scale 3 to irreversible Disability Status Scale 6. Outcome was assessed through five parameters: Phase 1 duration, age at Disability Status Scale 3, time to Disability Status Scale 6 from multiple sclerosis onset, Phase 2 duration and age at Disability Status Scale 6. The first three were calculated among all patients, while the last two were computed only among patients who had reached Disability Status Scale 3. The possible influence of early clinical markers on these outcomes was studied using Kaplan–Meier estimates and Cox models. The analysis was performed in the Rennes multiple sclerosis database (2054 patients, accounting for 26 273 patient-years) as a whole, and according to phenotype at onset (1609 relapsing/445 progressive onset). Our results indicated that the disability progression during Phase 2 was independent of that during Phase 1. Indeed, the median Phase 2 duration was nearly identical (from 6 to 9 years) irrespective of Phase 1 duration (<3, 3 to <6, 6 to <10, 10 to <15, ≥15 years) in the whole population, and in both phenotypes. In relapsing onset multiple sclerosis, gender, age at onset, residual deficit after the first relapse and relapses during the first 2 years of multiple sclerosis were found to be independent predictive factors of disability progression, but only during Phase 1. Our findings demonstrate that multiple sclerosis disability progression follows a two-stage process, with a first stage probably dependant on focal inflammation and a second stage probably independent of current focal inflammation. This concept has obvious implications for the future therapeutic strategy in multiple sclerosis.
The concept of induction followed by a long-term maintenance treatment has attracted much attention for the treatment of multiple sclerosis over the 30 past years. It was first demonstrated by the ...combination of induction therapy with mitoxantrone (six-monthly courses) followed by maintenance therapy with an immunomodulatory treatment such as an interferon-β or glatiramer acetate. Long-term observational studies confirmed that this therapeutic regimen provides a rapid reduction in disease activity and sustained disease control up to at least five years in 60% of patients. A better treatment response was observed in patients with early signs of aggressive disease, as shown in randomised studies (using six-monthly 12mg/m2 of mitoxantrone intravenously at a cumulative dose of 72mg/m2, followed by an interferon-β) as well as in long-term observational studies. But the safety profile of mitoxantrone make it more particularly suitable for young patients with frequent early relapses with incomplete recovery and multiple gadolinium-enhancing T1 lesions or spinal cord lesions on magnetic resonance imaging. More recently approved, the second candidate for an induction strategy is alemtuzumab: phases II and III randomised studies showed the superiority of alemtuzumab 12mg per day given intravenously for only five days and repeated for 3 days one year later, compared with interferon-β three times a week. Like with mitoxantrone, results supported the concept of long-term benefit after a short induction rather than escalation, in a subset of patients with early very active MS, with a sustained control of the disease for up to 7 years in 60% of patients in the phase III extension studies and in a long-term observational study. On the contrary, when alemtuzumab was first studied later in the disease course, results were disappointing. However, the risk of developing manageable but potentially severe systemic autoimmune diseases within the years following the last course of alemtuzumab make it, like mitoxantrone, more suitable for patients with early aggressive MS. More recently, cladribine an oral immunosuppressant, showed interesting results in a phase III study extension suggesting its potential induction effect, since after two cycles of treatment (5 days repeated 1 month later) at one year of interval, the remained low up to 4 years of follow-up, in the absence of any new treatment. However, today other immunosuppressive drugs have proved to be strongly and rapidly efficacious in treating highly active MS patients but through a mechanism of continuous immunosuppression (i.e., natalizumab and ocrelizumab). Indeed, disease activity can reappear rapidly after stopping these drugs, sometimes associated with a rebound of the inflammatory process, which is the contrary of a mechanism of induction that is associated with a remnant effect. Taking into account advantages and disadvantages of the different DMDs, which enriched the today therapeutic arsenal for MS, we propose in this paper some algorithms summarizing our reflexion about using an escalation strategy or an induction strategy according to disease course and activity.
The long-term impact of interferon-beta-1b (IFN) might be improved by short-term immunosuppression with mitoxantrone (MITOX) in aggressive relapsing-remitting multiple sclerosis (ARMS) patients.
In ...this 3-year clinical and MRI study, 109 ARMS patients (two or more relapses in the previous 12 months and one or more gadolinium (Gd)-enhancing MRI lesion) were randomised into two groups: 54 patients received MITOX monthly (12 mg/m(2); maximum 20 mg) combined with 1 g of methylprednisolone (MP) for 6 months followed by IFN for the last 27 months, and 55 patients received IFN for 3 years combined with 1 g of MP monthly for the first 6 months. The primary endpoint was the time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months.
The time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months was delayed by 18 months in the MITOX group compared with the IFN group (p<0.012). The 3-year risk of worsening disability was reduced by 65% in the MITOX group relative to the IFN group (11.8% vs 33.6%). MITOX patients had a reduced relapse rate by 61.7%, a reduced number of Gd-enhancing lesions at month 9 and a slower accumulation of new T2 lesions at each time point.
Although there were limitations in this investigator-academic-driven study, the data do suggest that mitoxantrone induction therapy prior to INF beta-1b may have a role in aggressive disease.
To assess whether modafinil, a wakefulness-promoting agent, is useful for fatigue in patients with multiple sclerosis (MS).
Patients with MS with stable disability, and a baseline score of 45 or more ...on the Modified Fatigue Impact Scale (MFIS), were eligible for the 5-week randomized, double-blind, placebo-controlled, parallel group study. The initial daily dose of modafinil was 200 mg for 1 week. Depending on tolerance, the dose was increased by 100 mg every week up to 400 mg/day and remained unchanged between day 21 and day 35. The primary outcome variable was the change of MFIS score at day 35.
A total of 115 patients with MS were enrolled in the study and in the intention to treat analysis. The mean MFIS score at baseline was 63 +/- 9 in the placebo group and 63 +/- 10 in the modafinil group. MFIS scores improved between day 0 and day 35 in both placebo-treated and modafinil-treated groups, but no significant difference was detected between the two groups. There was no major safety concern.
There was no improvement of fatigue in patients with multiple sclerosis treated with modafinil vs placebo according to the Modified Fatigue Impact Scale.
To assess efficacy, safety, and tolerability of every-other-day interferon beta-1b treatment in patients with a first clinical event suggestive of multiple sclerosis (MS) (clinically isolated ...syndrome).
We conducted a multicenter, randomized, double-blind, placebo-controlled trial. Patients with a first clinical demyelinating event and at least two clinically silent brain MRI lesions were randomized to interferon beta-1b (IFNB-1b) 250 mug subcutaneously (SC) every other day (EOD) (n = 292) or placebo (n = 176), until clinically definite MS (CDMS) was diagnosed or they had been followed for 24 months.
After 2 years, 45% of placebo patients had converted to CDMS (Kaplan-Meier estimate; primary outcome measure) and 85% fulfilled the McDonald criteria (co-primary outcome measure). Overall interferon beta-1b delayed the time to diagnosis of CDMS (p < 0.0001) and McDonald MS (p < 0.00001). Hazard ratios (95% CI) were 0.50 (0.36 to 0.70) for CDMS and 0.54 (0.43 to 0.67) for McDonald MS favoring treatment with IFNB-1b. Treatment was well tolerated, as indicated by the low rate of patients dropping out of the study before CDMS was reached (6.6% overall, 7.2% in the IFNB-1b group).
Interferon beta-1b 250 mug subcutaneously every other day delayed conversion to clinically definite multiple sclerosis, and should be considered as a therapeutic option in patients presenting with a first clinical event suggestive of multiple sclerosis.
Background and purpose
The benefits of immunomodulatory treatments in secondary progressive multiple sclerosis (SPMS) are unclear, calling into question their continuation. In the present ...observational study, we investigated the effect of treatment withdrawal on the clinical course of SPMS.
Methods
We included 100 consecutive patients with SPMS who regularly attended our multiple sclerosis clinic. Inclusion criteria were (i) secondary progressive phenotype for at least 2 years, (ii) immunomodulatory treatment for at least 6 months and (iii) treatment stopped with no plans to switch to another. Clinical and magnetic resonance imaging (MRI) data before and after treatment discontinuation were assessed. Factors associated with relapses and/or MRI activity were identified.
Results
Mean treatment duration was 60.4 ± 39.3 months, and mean follow‐up duration after treatment withdrawal was 62.4 ± 38.4 months. The annualized relapse rate remained stable at 1 and 3 years after treatment withdrawal 0.09, 95% confidence interval (CI), 0.05–0.17 and 0.07, 95% CI, 0.05–0.11, respectively, relative to the 3 years prior to treatment withdrawal (0.12, 95% CI, 0.09–0.16). Sixteen patients experienced a relapse and 19 had a gadolinium‐positive MRI scan without relapse during follow‐up. A gadolinium‐positive MRI scan within the previous 3 years before treatment withdrawal and Expanded Disability Status Scale score of <6 were positively associated with relapse and/or MRI activity after discontinuation (P = 0.0004 and P = 0.03, respectively).
Conclusion
In this retrospective study, including a limited number of patients with SPMS, the annualized relapse rate remained stable after treatment withdrawal, relative to before treatment withdrawal. Further prospective studies are needed to confirm this result and provide evidence‐based guidelines for daily practice.
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